U.S. patent number 6,423,341 [Application Number 09/117,295] was granted by the patent office on 2002-07-23 for .beta.-lactam antibiotic-containing tablet and production thereof.
This patent grant is currently assigned to Fujisawa Pharmaceutical Co., Ltd.. Invention is credited to Hisami Yamaguchi.
United States Patent |
6,423,341 |
Yamaguchi |
July 23, 2002 |
.beta.-lactam antibiotic-containing tablet and production
thereof
Abstract
This invention provides .beta.-lactam antibiotic-containing
tablets capable of being orally taken either as such owing to their
being small-sized, hence still easily swallowable, or, in the case
of administration to the aged encountering some difficulty in
swallowing, in the form of dispersions resulting from easy
self-disintegration upon being dropped into water in a glass as
well as a method of producing the same. The tablets of this
invention comprise, on the per-tablet basis, 60-85% by weight of a
.beta.-lactam antibiotic, 1-10% by weight of low-substituted
hydroxypropylcellulose and/or crosslinked polyvinylpyrrolidone as a
disintegrator, and 0.5-2% by weight of a binder. Granules to be
compressed for tableting are prepared using water or an aqueous
solution of ethanol or the like.
Inventors: |
Yamaguchi; Hisami (Osaka,
JP) |
Assignee: |
Fujisawa Pharmaceutical Co.,
Ltd. (Osaka, JP)
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Family
ID: |
26382481 |
Appl.
No.: |
09/117,295 |
Filed: |
August 26, 1998 |
PCT
Filed: |
February 21, 1997 |
PCT No.: |
PCT/JP97/00509 |
371(c)(1),(2),(4) Date: |
August 26, 1998 |
PCT
Pub. No.: |
WO97/31639 |
PCT
Pub. Date: |
September 04, 1997 |
Foreign Application Priority Data
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Feb 29, 1996 [JP] |
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8-042743 |
Nov 29, 1996 [JP] |
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8-320264 |
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Current U.S.
Class: |
424/465; 424/464;
514/960; 514/961 |
Current CPC
Class: |
A61K
31/546 (20130101); A61K 31/545 (20130101); A61K
9/2013 (20130101); A61P 31/00 (20180101); A61K
9/0056 (20130101); A61P 31/04 (20180101); A61K
9/2027 (20130101); A61K 9/0095 (20130101); A61K
9/2054 (20130101); Y10S 514/96 (20130101); Y10S
514/961 (20130101) |
Current International
Class: |
A61K
31/545 (20060101); A61K 31/546 (20060101); A61K
9/00 (20060101); A61K 9/20 (20060101); A61K
009/20 () |
Field of
Search: |
;424/464,465,466
;514/960,961,200,202,210,215 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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0 599 767 |
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Jun 1994 |
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EP |
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2 669 221 |
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May 1992 |
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FR |
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Primary Examiner: Page; Thurman K.
Assistant Examiner: Seidleck; Brian K.
Attorney, Agent or Firm: Oblon, Spivak, McClelland, Maier
& Neustadt, P.C.
Parent Case Text
This application is a 371 of PCT/JP97/00509, filed Feb. 21, 1997.
Claims
What is claimed is:
1. A pharmaceutical tablet which can be swallowed whole or rapidly
disintegrated in water, comprising at least 300 mg potency and from
60% to 85% by weight of a .beta.-lactam antibiotic, a sweetener, 1
to 10% by weight of hydroxypropylcellulose having a degree of
substitution with 2-hydroxypropoxy groups of not higher than 25%
and/or crosslinked polyvinylpyrrolidone as a disintegrator and 0.8
to 2% by weight of a binder per tablet, wherein said tablet is made
with a granulation product prepared from the .beta.-lactam
antibiotic disintegrator, binder and an alcohol selected from the
group consisting of ethanol, isopropyl alcohol and aqueous
solutions thereof.
2. A tablet as claimed in claim 1, wherein the binder is
polyvinylpyrrolidone, hydroxypropylcellulose or
hydroxypropylmethylcellulose.
3. A tablet as claimed in claim 1 which further comprises 0.5 to
15% by weight of a synthetic sweetener and/or a granulated
synthetic sweetener.
4. A tablet as claimed in claim 3, wherein the synthetic sweetener
or the granulated synthetic sweetener has an mean particle size of
not less than 150 .mu.m.
5. A tablet as claimed in claim 4, wherein the synthetic sweetener
or the granulated synthetic sweetener, is not less than 150 .mu.m
in particle size.
6. A tablet as claimed in claim 3, wherein the granulated synthetic
sweetener comprises a synthetic sweetener, and light anhydrous
silicic acid and/or hydrated silicon dioxide.
7. A tablet as claimed in claim 1 , wherein the .beta.-lactam
antibiotic is cefixime or cefdinir.
8. A tablet as claimed in claim 7 which contains 400 mg potency of
cefixime, the tablet weight being not greater than 650 mg.
9. A tablet as claimed in claim 7 which contains 300 mg potency of
cefdinir, the tablet weight being not greater than 450 mg.
10. A method of producing .beta.-lactam antibiotic-containing
tablets which comprises admixing a synthetic sweetener and/or a
granulated synthetic sweetener, optionally together with one or
more other additives, with a granulation product prepared from the
.beta.-lactam antibiotic, disintegrator and binder specified in
claim 1, optionally together with one or more excipients, by using
ethanol, isopropyl alcohol or an aqueous solution of ethanol or
isopropyl alcohol, and then tableting the resulting mixture.
Description
TECHNICAL FIELD
This invention relates to .beta.-lactam antibiotic-containing
tablets and a method of producing the same. More particularly, it
relates to tablets of the above variety which can be orally taken
either as such or, for taking by, for example, the aged who have
difficulties in swallowing, as a dispersion available upon dropping
the same into water in a glass for self-disintegration, and to a
method of producing the same.
BACKGROUND TECHNOLOGY
Particularly in Europe and America, where .beta.-lactam.
antibiotics such as cefixime and cefdinir are administered
generally in single doses of as great as 200 mg to 400 mg potency,
unit dosage forms, whether they are capsules or tablets, have to be
considerably large in size. When 400 mg potency capsules are
prepared, for instance, the capsule size reaches approximately No.
0, so that not only patients having difficulties in swallowing but
also ordinary adult patients become reluctant to take them or get a
repulsive sensation in taking them. Such capsules are indeed
difficult to take. In the case of tablets, too, 400 mg potency
tablets generally weigh 700 to 1,000 mg per tablet and accordingly
are large-sized.
The problems encountered in taking such large dosage forms give an
unnecessary sensation of oppression to patients on the occasion of
taking them. Improvements in their administrability have thus been
required.
Therefore, the present inventor attempted to provide a dosage form
with improved administrability by reducing the tablet size as much
as possible to thereby facilitate the taking of tablets by the
recipient and at the same time to provide a dosage form capable of
being taken in the form of a dispersion resulting from rapid
self-disintegration upon its being simply dropped into water or the
like in a glass, for instance, to thereby make said dosage form
administrable to persons of advanced age or children having
difficulties in swallowing the dosage form as such. The expression
"rapid self-disintegration" as used herein means that when the
preparation is dropped into a glass containing a liquid such as
water, the tablet form spontaneously collapses generally within 3
minutes, preferably within 1 minute, so that said preparation can
be orally taken in dispersion form without awaiting long before
taking.
It is indeed easy to produce tablets capable of self-disintegrating
very rapidly by incorporating an effervescent agent comprising a
combination of sodium hydrogen carbonate and tartaric acid, for
instance. However, when such tablets are orally taken, they give
off bubbles in the oral cavity, so that patients feel a discomfort
or an unnecessary sensation of anxiety. For securing a good
shelf-life in a humid environment, it is necessary to use a
moisture-proof packaging material, which increases the production
cost. Therefore, in developing the dosage form which the present
invention is intended to provide, it has been a tough problem to
find out a formulation enabling very rapid self-disintegration
without the aid of any effervescent component.
For producing .beta.-lactam antibiotic-containing tablets which can
be easily ingested as they are and be also ingested in the form of
a dispersion resulting from self-disintegration thereof, a
technology is described in European Patent EP 0281200 B
(corresponding Japanese patent application: Kokai Tokkyo Koho
S63-301820), which comprises adding 24 to 70% by weight, based on
the weight of the .beta.-lactam antibiotic, of microcrystalline
cellulose or microfine cellulose as a first disintegrator and 2 to
20% by weight, on the same basis, of low-substituted
hydroxypropylcellulose or the like as a second disintegrator.
However, said first disintegrator, which is used in a large amount,
increases the tablet size. In addition, the proportion of a binder
component for wet granulation is as low as 0 to 0.1% by weight
based on the antibiotic, hence is substantially nil. This is
because the use of a binder renders tablets extremely poor in
self-disintegrating properties. In the process for producing these
tablets, in which no binder is used, a special method of insuring
an integrity of the artefact is employed which comprises mixing the
antibiotic bulk substance with microcrystalline cellulose and
kneading the mixture with the aid of water under application of a
great deal of force, without using any alcohol. As a result, large
lumps are formed inevitably and they are milled in the wet state
and then dried, followed by further milling to provide granules for
tableting. It is a problem that these steps are very
inefficient.
Meanwhile, tablets containing amoxicillin, which is a .beta.-lactam
antibiotic, are commercially available under the trade name of
Flemoxin Solutab 500 from Brocades Pharma (Netherlands), the
patentee to whom said European patent has been granted. Said
tablets each contains 500 mg potency (about 570 mg) of amoxicillin
and weighs about 970 mg, hence is very large and not entirely
suited for oral administration.
Most .beta.-lactam antibiotics are bitter. Therefore, aqueous
dispersions prepared from tablets containing them, when orally
taken, give a bitter taste, although the tablets, when taken as
such, taste not so bitter. For masking the bitter taste, it thus
becomes necessary to incorporate a sweetener, preferably a
synthetic sweetener which is effective at low addition levels and
thus suited for tablet miniaturization. However, when a commercial
synthetic sweetener is incorporated, a problem arises, namely the
self-disintegrating properties of tablets become poor, since
synthetic sweeteners are soluble in water and become viscous and
sticky.
DISCLOSURE OF THE INVENTION
In an attempt to develop a method of improving the rate of
self-disintegration of tablets and at the same time miniaturizing
the same, the present inventor made investigations concerning the
disintegrator species to be used, the level of addition thereof,
the binder addition level, the synthetic sweetener particle size
and the method of incorporating the same, among others and, as a
result, the inventor invented .beta.-lactam antibiotic-containing
tablets which are small-sized, show good self-disintegrating
properties and can be produced by a conventional method.
Furthermore, the inventor found that when granulation is performed
using ethanol, isopropyl alcohol or an aqueous solution of ethanol
or isopropyl alcohol, tablets showing better dispersibility upon
self-disintegration can be obtained.
The .beta.-lactam antibiotic-containing tablets of this invention
contain, per tablet, 60 to 85% by weight of an .beta.-lactam
antibiotic, 1 to 10% by weight of low-substituted
hydroxypropylcellulose and/or crosslinked polyvinylpyrrolidone as a
disintegrator, and 0.5 to 2% by weight of a binder.
Preferably, the .beta.-lactam antibiotic-containing tablets of this
invention further contain, per tablet, 0.5 to 15% by weight of a
synthetic sweetener and/or a granulated synthetic sweetener.
The .beta.-lactam antibiotic-containing tablet production method of
this invention is characterized in that the above-specified
respective proportions of a .beta.-lactam antibiotic, the
disintegrator and a binder, optionally together with one or more
excipients, are granulated using ethanol, isopropyl alcohol or an
aqueous solution of ethanol or isopropyl alcohol, the granulation
product is mixed with the above-specified proportion of a synthetic
sweetener and/or a granulated synthetic sweetener, optionally
together with one or more other additives, and the resulting
mixture is compressed.
The .beta.-lactam antibiotic to be used in the practice of this
invention is one capable of producing a beneficial effect upon oral
administration and includes, for example, cefixime and cefdinir
respectively represented by the structural formulas shown below as
well as cefaclor, cefroxadine, cefadroxil, cefaloglycin, cefalexin,
cefradine, amoxicillin, ampicillin and the like. ##STR1##
Each tablet contains such .beta.-lactam antibiotic in a proportion
of 60 to 85% by weight, preferably 65 to 80% by weight.
As a result of investigations concerning the disintegrator species
to be used in the practice of this invention and the level of
addition thereof, it was found that, as compared with such salt
type disintegrators as ECG 505 (trademark; carboxymethylcellulose
calcium), Ac-Di-Sol (trademark; crosslinked carboxymethylcellulose
sodium) and Primojel (trademark; starch glycolic acid sodium),
nonion type disintegrators, such as low-substituted
hydroxypropylcellulose (L-HPC) and crosslinked
polyvinylpyrrolidone, can produce a very good disintegrating effect
even when they are added in small proportions. Low-substituted
hydroxypropylcellulose is a product derived from cellulose by
partial substitution with the 2-hydroxypropoxy group, the degree of
substitution being not higher than 25%, preferably 7 to 16%.
Generally, low-substituted hydroxypropylcellulose and crosslinked
polyvinylpyrrolidone are incorporated in tablets independently,
although both may be used combinedly.
Such disintegrator is used in a proportion of 1 to 10% by weight,
preferably 3 to 8% by weight, on a per-tablet basis.
The tablets of this invention further contain binder as an
essential constituent. The addition of a binder has an adverse
effect on the self-disintegrating properties of tablets, hence is
not desirable from the self-disintegration viewpoint. However, the
production of tablets without adding any binder give such
inconveniences as mentioned herein-before.
The inventor of this invention made investigations in search of
binder species which would not give adverse effects on the
self-disintegrating properties of tablets as well as investigations
concerning the addition level thereof. As preferred binders, there
may now be mentioned, for example, polyvinylpyrrolidone,
hydroxypropylcellulose, preferably low-viscosity type (L-type)
hydroxypropylcellulose, hydroxy-propylmethylcellulose,
methylcellulose, starch, pregelatinized starch, partly
pregelatinized starch, gum arabic, dextrin, pullulan and the like.
Among these binders, polyvinylpyrrolidone, hydroxypropylcellulose
and hydroxypropylmethylcellulose are more preferred, and
polyvinylpyrrolidone is most preferred. When these binders are used
in an amount of 0.5 to 2% by weight, preferably 0.8 to 1.5% by
weight, on a per-tablet basis, tablets which can self-disintegrate
rapidly can be produced by a conventional production method.
Since .beta.-lactam antibiotics, for example cefixime and cefdinir,
have a strongly bitter taste, it is necessary to add a synthetic
sweetener in cases where tablets are to be taken in the form of
dispersions after self-disintegration in water, for instance,
though this is not always necessary in cases where tablets are to
be taken as such.
As regards the synthetic sweetener addition level, which may vary
according to the synthetic sweetener species and the active
ingredient .beta.-lactam antibiotic, the sweetener is incorporated
in tablets generally in a proportion of 0.5 to 15% by weight,
preferably 1 to 10% by weight.
The commercial synthetic sweetener products are generally small,
i.e. less than 150 .mu.m, in mean particle size, with particle not
smaller than 150 .mu.m accounting for at most 4% of the whole.
Incorporation of such products markedly reduces the rate of
disintegration of tablets. To improve the disintegration rate, the
prior art employs a method which comprises incorporating a large
amount of an excipient such as microcrystalline cellulose. However,
incorporation of a large amount of such excipient according to said
method results in an increase in tablet size, thereby making the
tablets difficult to take with ease. The present inventor found
that when the particle size of a synthetic sweetener is increased
or when a granulated mixture of a synthetic sweetener and light
anhydrous silicic acid, hydrated silicon dioxide or the like is
added, the rate of disintegration can be improved, namely prevented
from retardation.
As a result, an invention was made of miniaturized tablets which
can be easily taken as such and, when dropped into water in a
glass, can rapidly self-disintegrate, enabling administration
thereof in dispersion form.
When such a synthetic sweetener as saccharin, a salt thereof (e.g.
saccharin calcium, saccharin sodium), cyclamic acid or a salt
thereof (e.g. sodium cyclamate, calcium cyclamate, ammonium
cyclamate) is used, said sweetener is required to be not less than
150 .mu.m in mean particle size, preferably not less than 150 .mu.m
in particle size. In the case of a sweetener capable of producing a
satisfactory bitter-masking effect in small amounts, for example
aspartame, it is not always necessary that the mean particle size
be not less than 150 .mu.m, since the disintegrability of tablets
is little affected.
The synthetic sweetener may be incorporated either in the form of
crystalline grains having a mean particle size of not less than 150
.mu.m or in the form of a granulation product meeting the particle
size requirement as obtained by wet granulation from the
powder-form small in mean particle size or by wet granulation or
dry granulation from such powder together with a color additive
and/or microcrystalline cellulose or a like excipient.
The granulation product containing light anhydrous silicic acid or
hydrated silicon dioxide in addition to a synthetic sweetener can
be produced by mixing the synthetic sweetener with 1 to 30% by
weight, relative to the synthetic sweetener weight, of light
anhydrous silicic acid or hydrated silicon dioxide and granulating
the mixture in the conventional manner, if necessary using a binder
and/or one or more other additives in common use. It was found that
in the case of granulation products containing a synthetic
sweetener together with light anhydrous silicic acid or hydrated
silicon dioxide, the particle size is not critical, with the result
that the self-disintegrating properties are never adversely
affected even when the mean particle size is below 150 .mu.m. As
regards other ingredients to be used in producing the tablets of
this invention, the same ingredients or additives as used
conventionally in the production of solid preparations may be
mentioned. Thus, in addition to the above-mentioned synthetic
sweetener or granulated synthetic sweetener, excipients such as
microcrystalline cellulose, lactose, mannitol, starch, etc.,
flowability improvers such as light anhydrous silicic acid,
hydrated silicon dioxide, etc., lubricants such as magnesium
stearate, stearic acid, talc, etc., flavoring agents and other
agents may be incorporated unless the self-disintegrating
properties are adversely affected. When the .beta.-lactam
antibiotic has a large particle size, it may be ground prior to
use. In this case, however, wet or dry granulation is required to
improve the powder flowability in the step of compression.
In a preferred process for producing the tablets of the present
invention, the above-specified disintegrator and binder, optionally
together with other ingredients, are added to the .beta.-lactam
antibiotic, the mixture is granulated by a conventional method, the
above-mentioned synthetic sweetener and/or granulated synthetic
sweetener, optionally together with one or more other ingredients
(e.g. flowability improver, lubricant, flavor), are then further
added, and the resulting mixture is subjected to tableting.
When, in the above production process, water is used for
granulation in the granulation step, tablets with good
self-disintegrating properties are generally obtained. In this
connection, the inventor of this invention further found that when
ethanol, isopropyl alcohol or a mixture of water and ethanol or
isopropyl alcohol is used for granulation, tablets with good
self-disintegrating properties and with very good dispersibility
upon allowing dispersion in water can be obtained. The
concentration of the aqueous solution of ethanol or isopropyl
alcohol, which is suited for use, is 3 to 99% (volume/volume),
preferably 10 to 60% (volume/volume).
INDUSTRIAL APPLICABILITY
The thus-obtained .beta.-lactam antibiotic-containing tablets of
this invention are small in size. For example, a tablet containing
400 mg potency (about 449 mg) of cefixime may weigh not more than
650 mg and a tablet containing 300 mg potency (about 307 mg) of
cefdinir not more than 450 mg. They can be orally taken as such
with ease. When they are to be taken by the aged, for instance,
complaining of some difficulty in swallowing, in an aqueous
dispersion form, the tablets can be rapidly disintegrated and
dispersed in water.
Moreover, the use of ethanol, isopropyl alcohol or an aqueous
solution of ethanol or isopropyl alcohol for granulation in the
granulation step makes it possible to obtain tablets with still
better dispersibility in water.
Test Example 1 (Disintegrator Effect)
According to the formulation shown below in Table 1, cefixime bulk
substance, microcrystalline cellulose, one of the disintegrators,
light anhydrous silicic acid and magnesium stearate, taken in the
respective specified proportions, were mixed up and the mixture was
compressed on a single-punch tablet machine to give tablets having
a diameter of 11 mm.
The tablets produced by the above method were evaluated for
disintegration time in 1,000 ml of water (20.+-.1.degree. C.) using
a Japanese Pharmacopeia disintegration tester, but without using
any disk, with 30 cycles per minute of basket ascending and
descending. The disintegration time data thus obtained are shown in
Table 2.
TABLE 1 Cefixime bulk substance 448.9 (400 mg potency)
Microcrystalline cellulose 38.9 Disintegrator 38.9 Light anhydrous
silicic acid 1.2 Magnesium stearate 5.9 Total 533.8 mg
TABLE 2 Disintegration time (min.) Disintegrator n = 6
Carboxymethylcellulose 1.2-1.3 calcium Starch glycolic acid 1.0-1.2
sodium Crosslinked carboxymethyl- 0.8-1.1 cellulose sodium
Low-substituted 0.3-0.4 hydroxypropylcellulose Crosslinked
polyvinyl- 0.3-0.4 pyrrolidone
As is evident from Table 2, those tablets which contain
low-substituted hydroxypropylcellulose or crosslinked
polyvinylpyrrolidone in accordance with the present invention
disintegrate very rapidly.
Test Example 2 (Binder Study)
According to the formulation shown below in Table.3, cefixime bulk
substance micronized by a pin-type mill, microcrystalline cellulose
and one of the binders, together with 50% (by volume) ethanol, were
granulated in a high speed shear mixer, followed by drying under
flowing air at 40.degree. C. for 17 hours and sizing through a
500-.mu.m sieve. The granules sieved out were mixed with
low-substituted hydroxypropylcellulose, light anhydrous silicic
acid and magnesium stearate, in the respective specified
proportions, followed by compression on a single-punch tablet
machine, to give tablets each having the specified weight and a
diameter of 11 mm.
The tablets produced by the above method were evaluated for
disintegration time under the same conditions as in Test Example 1.
The disintegration time data thus obtained are shown in Table
4.
TABLE 3 Cefixime 448.9 (400 mg potency) Microcrystalline cellulose
38.9 Binder 4.9 (14.6) Low-substituted 38.9 hydroxypropylcellulose
Light anhydrous silicic acid 1.2 Magnesium stearate 5.9 Total 538.7
mg (548.4 mg)
TABLE 3 Cefixime 448.9 (400 mg potency) Microcrystalline cellulose
38.9 Binder 4.9 (14.6) Low-substituted 38.9 hydroxypropylcellulose
Light anhydrous silicic acid 1.2 Magnesium stearate 5.9 Total 538.7
mg (548.4 mg)
As is evident from Table 4, the tablets produced by using
polyvinylpyrrolidone, hydroxypropylcellulose (L type) or
hydroxypropylmethylcellulose as the binder disintegrate
rapidly.
Test Example 3 (Synthetic Sweetener Particle Size Study)
According to the formulation shown below in Table 5, cefixime bulk
substance micronized by a pin-type mill, microcrystalline
cellulose, low-substituted hydroxypropylcellulose and
polyvinylpyrrolidone, together with 50% (by volume) ethanol, were
granulated in a high speed shear mixer, followed by drying under
flowing air at 40.degree. C. for 17 hours and sizing using a
500-.mu.m sieve. The granules sieved out were mixed with light
anhydrous silicic acid, magnesium stearate, strawberry powder
flavor and commercial saccharin calcium, the large particle size
saccharin calcium prepared in Example 1 to be mentioned later
herein or the granulated mixture of saccharin calcium and light
anhydrous silicic acid prepared in Example 2 to be mentioned later
herein, in the respective specified proportions, followed by
compressing on a single-punch tablet machine to give tablets each
having the specified weight and a diameter of 11 mm.
The tablets produced by the above method were evaluated for
disintegration time under the same conditions as in Test Example 1.
The disintegration time data thus obtained are shown in Table
6.
TABLE 5 Cefixime 448.9 (400 mg potency) Microcrystalline cellulose
38.9 Low-substituted 38.9 hydroxypropylcellulose
Polyvinylpyrroridone 4.9 Light anhydrous silicic acid 1.2 Magnesium
stearate 5.9 Strawberry powder flavor 7.5 Saccharin calcium or 20.0
granulated saccharin calcium Total 566.2 mg
TABLE 5 Cefixime 448.9 (400 mg potency) Microcrystalline cellulose
38.9 Low-substituted 38.9 hydroxypropylcellulose
Polyvinylpyrroridone 4.9 Light anhydrous silicic acid 1.2 Magnesium
stearate 5.9 Strawberry powder flavor 7.5 Saccharin calcium or 20.0
granulated saccharin calcium Total 566.2 mg
As is evident from Table 6, the tablets produced by using the
saccharin calcium not less than 150 .mu.m in particle size or the
granulated mixture of saccharin calcium and light anhydrous silicic
acid are positively shorter in disintegration time than the tablets
produced by using the commercial saccharin calcium smaller than 150
.mu.m in mean particle size.
Test Example 4 (Influence of the Composition of the Solution for
Granulation on the Dispersibility of Tablets)
A 2,200 ml portion of water or an aqueous solution of ethanol was
used to granulate a mixture of 4,566 g of cefixime bulk substance
micronized by a pin-type mill, 405 g of microcrystalline cellulose,
405 g of low-substituted hydroxypropylcellulose and 50.6 g of
polyvinylpyrrolidone in a high speed shear mixer and, after drying
under flowing air at 40.degree. C. for 17 hours, the granulation
product was sized using a 500-.mu.m sieve. The granules sieved out
were mixed with 50.6 g of light anhydrous silicic acid, 101.2 g of
magnesium stearate, 75.9 g of strawberry powder flavor and 202.6 g
of saccharin calcium (particle size: 150-840 .mu.m), followed by
compressing on a rotary tablet machine to give oblong tablets each
weighing 579 mg.
The tablets produced by the above method were evaluated, by the
method mentioned below, for disintegration time as well as for
dispersibility for use in dispersion form.
Disintegration Time
The disintegration time evaluation was made in 1,000 ml of water
(20.+-.1.degree. C.) using a Japanese Pharmacopeia disintegration
tester, but without using any disk, with 30 cycles per minute of
basket ascending and descending.
Dispersibility After Standing of Dispersions Prepared
One tablet was dropped into 20 ml of water placed in a 50-ml beaker
and the whole was allowed to stand for 5 minutes for
self-disintegration. Then, the beaker was shaken gently for
stirring and thereafter allowed to stand for 1 minute, followed by
observation of the appearance.
TABLE 7 Disintegration Dispersibility time (sec.) after standing
Granulation 39 a using 50% ethanol Granulation 84 a using 10%
ethanol Granulation 62 b using water Flemoxin Solutab 500 46 b
(commercial product) a:Wholly uniform in color, substantially
without any precipitate. b:A supernatant and a slight amount of a
precipitate.
The tablets derived from the granules prepared using ethanol are
still better in dispersibility after standing as compared with
those derived from the granules prepared using water.
Test Example 5 (Disintegration Test) Test preparations A: Tablets
produced in Example 1 to be mentioned later. B: Tablets produced in
Example 7 to be mentioned later. C: Tablets produced in Example 8
to be mentioned later.
Test Method
The disintegration time evaluation was performed in distilled water
at 20.+-.1.degree. C. with 4 cycles per minute of basket ascending
and descending, using an apparatus prescribed in the Japanese
Pharmacopeia (12th edition) under Disintegration Test.
Test Results A: 1.13 minutes B: 1.30 minutes C: 1.02 minutes
The disintegration test results indicate that the test preparations
A to C of this invention each shows good disintegrability.
EXAMPLE
Example 1
Water was added to saccharin calcium and the mixture was granulated
by a conventional method, followed by drying, sieving and sizing to
give saccharin calcium granules not less than 150 .mu.m in particle
size.
According to the formulation shown below, micronized cefixime bulk
substance, microcrystalline cellulose, low-substituted
hydroxypropylcellulose (L-HPC) and polyvinylpyrrolidone were
weighed and mixed together, water was then added, and the mixture
was granulated. The granulation product was dried under flowing air
at 40.degree. C. for 17 hours and then sized using a 500-.mu.m
sieve. The granules sieved out were mixed with magnesium stearate,
light anhydrous silicic acid, strawberry flavor and the
above-mentioned granulated saccharin calcium according to the
formulation shown below, followed by compressing on a single-punch
tablet machine to give tablets each having the specified
weight.
TABLE 8 Micronized cefixime bulk 448.9 mg (400 mg potency)
substance Microcrystalline cellulose 38.9 mg (Avicel .TM. PH101;
Asahi Chemical Industry) L-HPC 38.9 mg (LH-21; Shin-Etsu Chemical)
4.9 mg Polyvinylpyrrolidone (Kollidon .TM. 30; BASF) Light
anhydrous silicic acid 1.2 mg (Aerosil .TM.; Tomita Seiyaku)
Magnesium stearate 5.9 mg Saccharin calcium 20.0 mg (not less than
150 .mu.m in particle size) Strawberry flavor 7.5 mg Total 566.2
mg
Example 2
Saccharin calcium and light anhydrous silicic acid were mixed
together in a ratio of 20:1 and then water was added. The resultant
mixture was granulated by a conventional method, followed by drying
and sizing to give a granulated mixture of saccharin calcium and
light anhydrous silicic acid (75-500 .mu.m in particle size).
Then, tablets were produced following the procedure of Example 1
except that 21 mg of the above granulated mixture was used in lieu
of 20 mg of saccharin calcium (Example 1, Table 8).
Example 3
Saccharin calcium and hydrated silicon dioxide were mixed together
in a ratio of 20:1 and then water was added. The resultant mixture
was granulated by a conventional method, followed by drying and
sizing to give a granulated mixture of saccharin calcium and
hydrated silicon dioxide (75-500 .mu.m in particle size).
Then, tablets were produced following the procedure of Example 1
except that 21 mg of the above granulated mixture was used in lieu
of 20 mg of saccharin calcium (Example 1, Table 8).
Example 4
Tablets each containing 400 mg (potency) of cefixime were produced
in the same manner as in Example 1 except that L-HPC of Example 1
(Table 8) was replaced by the same amount of crosslinked
polyvinylpyrrolidone (Kollidon.TM. CL; BASF).
Example 5
Tablets each containing 400 mg (potency) of cefixime were produced
in the same manner as in Example 1 except that polyvinylpyrrolidone
of Example 1 (Table 8) was replaced by the same amount of
hydroxypropylcellulose (HPC-L; Nippon Soda).
Example 6
Tablets each containing 400 mg (potency) of cefixime were produced
in the same manner as in Example 1 except that polyvinylpyrrolidone
of Example 1 (Table 8) was replaced by the same amount of
hydroxypropylmethylcellulose (TC-5R.TM.; Shin-Etsu Chemical).
Example 7
According to the same formulation as that shown in Example 1 (Table
8), micronized cefixime bulk substance, microcrystalline cellulose,
L-HPC and polyvinylpyrrolidone were weighed and mixed together, 50%
aqueous ethanol was added, and the mixture was granulated. The
granulation product was dried under flowing air at 40.degree. C.
for 17 hours and then sized using a 500-.mu.m sieve. The granules
sieved out were mixed with magnesium stearate, light anhydrous
silicic acid, strawberry flavor and the granulated saccharin
calcium prepared in Example 1 (not less than 150 .mu.m in particle
size) and the resultant mixture was compressed on a single-punch
tablet machine to give tablets having the same composition as that
in Example 1 (Table 8).
Example 8
According to the formulation shown below, cefdinir-containing
tablets were produced in the same manner as in Example 7.
TABLE 9 Micronized cefdinir bulk 306.8 mg (300 mg potency)
substance Microcrystalline cellulose 29.2 mg (Avicel PH101) L-HPC
29.2 mg (LH-21) Polyvinylprrolidone 3.7 mg (Kollidon 30) Light
anhydrous silicic acid 0.9 mg (Aerosil) Magnesium stearate 4.4 mg
Saccharin calcium 15.0 mg (not less than 150 .mu.m in particle
size) Strawberry flavor 5.6 mg Total 394.8 mg
* * * * *